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Women in Chemistry

Women in Chemistry C

harlotte Allerton is Chief Scientific Officer, Anti-Infectives, and Head of Medicine Design at Pfizer, where the oral therapeutic for COVID-19, Paxlovid, was discovered. !"#$%&'()

Like so many, Charlotte Allerton was inspired to pursue her chemistry degree by a particularly dynamic teacher at school. At the University of Nottingham, Charlotte developed a deep love of both organic chemistry and mathematics, but, upon graduation these two loves meant Charlotte was torn between pursuing a career as an actuary (maths) or in the pharmaceutical industry (chemistry). A visit to Pfizer in Kent clinched her decision: “I was attracted to the practical nature of the work and its link between the chemistry I’d learned and the potential to benefit human health,” she says.

Starting with Sandwich Charlotte’s career with Pfizer started at the Sandwich site in Kent where she worked in synthesis technologies. She then worked on medicinal chemistry programmes at sites in the UK and Japan (“an incredible experience”), before moving to Connecticut in 2012 to become Head of Pharmacokinetics, Dynamics & Metabolism (PDM). “PDM is really about how our body deals with drug molecules,” she explains. Since 2016, Charlotte has been based at Pfizer’s Cambridge, Massachusetts site as Head of Medicine Design, which she describes as a combination of medicinal chemistry, PDM, and Discovery Sciences, and where Charlotte’s experience, in-depth knowledge, and leadership have contributed to the successful design of many of Pfizer’s oral therapeutics.

Accepting the Heroes of Chemistry award on behalf of Pfizer’s Medicine Design team.

Paterson group Early in her career, Charlotte attended Jesus College where she earned a Master of Philosophy (MPhil). “I was becoming increasingly interested in the broader aspects of drug design and development, and I could see the advantages of having a deeper discipline knowledge,” she says. Charlotte spent a happy and productive year in Professor Ian Paterson’s organic synthesis group. “I had the advantage of being in industry and having the context of the application of organic chemistry in drug discovery, which made me hungry to learn as much as I could during my time there,” she says. Charlotte found the Department very welcoming. “Professor Steven Ley encouraged me to attend his problem sessions, and other academics allowed me to attend undergrad and grad lectures,” she recalls, “So I made the most of my time there, made friends for life, like I did at Nottingham, and remain grateful to the University of Cambridge.” Charlotte returned to Cambridge earlier this year to speak at Prof. Paterson’s retirement symposium. “I am indebted to Ian to this day for everything he invested in me, the mentorship he gave me, and the great things I learned from him and the other students in his group,” she says. In return, Paterson recalls Charlotte as being one of the best students he ever had.

Designing a COVID-19 treatment Charlotte explains that Pfizer’s Medicine Design team are focused on designing and selecting the molecules that will ultimately be taken into clinical development to treat disease. She points out: “The properties of a molecule are determined at the moment of conception – whether a molecule will get to the right place in the body, stay there long enough, be administered safely and and have the

therapeutic potential we want – all that rests in the molecule we select.” This challenge was clear when the team was asked to develop a treatment for the SARS-CoV-2 virus, which causes COVID-19. Charlotte explains: “Inside the cell, the SARS-CoV-2 virus releases viral RNA, which is translated into two large polyproteins. The main protease breaks them up into smaller proteins so they can go on to form some of the viral replication machinery.” Nucleoside inhibitors block viral replication, but Charlotte’s team, guided by research project leader and fellow Cambridge alum Dafydd Owen, decided to target the main protease (see page 20). “We decided to design a molecule that would block or inhibit the protease which, in turn, would prevent the breakup of the large polyproteins and essentially stop viral replication.” The team started with a molecule that had been designed at the Pfizer La Jolla site for the 2003 SARS coronavirus outbreak. “Unfortunately, it had been designed to be taken intravenously, and we wanted an oral therapeutic so we could treat early in disease and prevent people from progressing to very severe COVID-19 and hospitalisation,” she says. “Ultimately, in a four-month drug discovery programme, enabled by some very committed colleagues as well as many of our investments in artificial intelligence and structurebased drug design, we identified the molecule nirmatrelvir. It’s a very potent binder to the SARS-CoV-2 main protease, and in doing that it has great antiviral activity in cells.” Nirmatrelvir is co-administered with ritonavir, which boosts its level in the blood by blocking an enzyme in the

liver that breaks it down, to maximise clinical efficacy. Together nirmatrelvir and ritonavir make Pfizer’s oral therapeutic, Paxlovid. Paxlovid has gone on to achieve emergency authorisation in various countries around the world, including the UK. Pfizer’s Medicine Design team received an American Chemical Society 2022 Heroes of Chemistry award for this achievement. Charlotte says: “To us it’s another great example of the power of chemistry: a unique molecular structure potently inhibits the target in patients to have a positive impact on healthcare.”

Women and diversity in chemistry “Creating and working in an inclusive culture is so important to ensuring we can all do our best at work every day,” says Charlotte. “During my career, I have been greatly enabled by strong networks, coaches and mentors – both men and women – who have helped me progress and learn. “There is plenty of data available that shows diverse teams are the highest performing teams. Over the last couple of years, we have seen impressive work across industry and academia to develop therapeutics and vaccines for COVID-19, building on a foundation from years of scientific innovation, and I have reflected on the diversity of the teams that have enabled that work.”

“Creating and working in an inclusive culture is so important to ensuring we can all do our best at work every day.”

Putting the plan into action

r Dafydd Owen completed his PhD with Professor Steven Ley in 1998. He is now Senior Scientific Director, Medicinal Chemistry at Pfizer and was lead author of the 2021 Science paper which describes Pfizer’s oral COVID-19 treatment, Paxlovid.1

“In the Ley group, I learned all about how to make molecules from scratch, which was valuable training. In industrial medicinal chemistry, you must combine all that knowledge to make a molecule with a purpose in mind, with a function and a potential use,” says Dafydd. “But you can’t test them unless you can make them, which is what I learned at Cambridge.”

2003. That research had progressed as an intravenously delivered molecule, which is significantly different from the practicality of an oral drug. “My job was to lead and build the team from this starting point to a safe, effective oral therapy for SARS-CoV-2. Scientifically, the challenge was to transform an intravenous agent into an oral agent – to do this, we ended up having to change 75 percent of the structure. By September 2020, we knew we were on to something.”

After his PhD and a year of postdoctoral research, Dafydd joined Pfizer’s Sandwich site in 1999, where Charlotte Allerton, whom he had overlapped briefly with at Cambridge, had started a few years earlier (page 18). “The Pfizer Sandwich site had a particular reputation for medicinal chemistry excellence, and I wanted to work for the best,” he says. “I wasn’t wrong: Pfizer was leading a lot of the thinking in how industrial medicinal chemistry should be done at the time.” In 2011, Dafydd was given the opportunity to move to Cambridge, Massachusetts, where he started to focus on external collaborative work with universities and industrial consortia.

The team was able to harness Pfizer’s research and development strengths, and Dafydd ‘s team worked with Charlotte and others to guide the molecule through all the standard safety tests. “We started in March, made the molecule by July, and by September it was ready for scale up.”

“We started in March, made the molecule The new treatment started Phase 1 clinical trials in March 2021. “To get by July, and by to this point in less than a year by any September it was stretch is amazing,” says Dafydd. The pivotal Phase 2/3 clinical trial started in ready for scale up.” July 2021. Dafydd recalls the moment he heard the results of the clinical trials: “In November 2021, we learned that the external Data Monitoring Committee recommended we cease further enrollment into the trial due to the overwhelming efficacy observed. It was a very, very proud moment as you can imagine. I’m not ashamed to say that I cried.

Dafydd Owen

COVID-19 research Then came 2020 and a pandemic which shook the world. In early 2020, Pfizer announced it was working on a vaccine.

“It is a powerful situation for a chemist to have played a part in the invention of a molecule that can help the world in its fight against COVID-19.”

Dafydd recalls: “On a Friday in March, Charlotte asked me, if we were to do this, how would you do it and what would you need? I started mapping it out and by the following Monday morning we had a plan to put into action.”

Dafydd was lead author on the paper that shared the research story through the end of the Phase 1 studies, which was featured on the cover of Science magazine in December 2021. “It was an utterly unforgettable week.”

The research team Dafydd and Charlotte assembled faced a number of obstacles, not least of which was lockdown. “We were adjusting to the shock of being at home and running a programme in a completely unconventional way, with the lofty goal of discovering a drug in time to make a difference to the pandemic, a process which would normally take 13 years. I take my hat off to the people who were given special permission by the authorities to go into the labs in early 2020, when there was no vaccine.”

Dafydd says: “I’d like to reiterate Charlotte’s role in this. She is a modest individual, a great frontline scientist and a great research leader. It’s amazing to me that our paths crossed early in life at Cambridge when we were both just learning to be organic chemists.” “It’s an understatement to say it is special when your training has played a large part in saving lives.”

The research team started with a viral main protease inhibitor first identified by Pfizer in the SARS outbreak of

Dafydd R. Owen, Charlotte M.N. Allerton, et al, An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19, Science (2021) 374, Issue 6575, 1586-1593.